The overall goal of this project is to define the molecular events involved in the transformation of low grade lymphomas to more aggressive forms. We have chosen follicular lymphoma as our primary model because it is a homogeneous group characterized by a single molecular lesion (bcl-2 translocation and deregulation), because over 70% of these low grade lymphomas will evolve into a histologically distinct high grade lymphoma, and because it is the most common low grade lymphoma in the United States. We have accumulated a large series of progressed follicular lymphomas from patients that have had multiple biopsies over the course of their disease. The matched biopsies from individual patients are studied for a variety of phenotypic and genotypic characteristics. A major focus is to identify acquired alterations within genes that have been previously implicated in growth and cell cycle control (e.g.: MYC, P53, Rb and PCNA). Changes in expression levels are also studied. In order to identify additional genetic loci that may play a significant role in lymphoma progression, we are proceeding with the development of subtraction c-DNA libraries specific to the progressed follicular lymphoma cells from individual patients. Using this approach, we hope to identify additional critical genes that may be important to the progressed phenotype.